This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 4. The human genome encodes just over 500 protein kinases. These kinases catalyze the transfer of the gamma phosphate of ATP to a specific hydoxyl group onto their target protein. This phosphorylation event can induce conformational changes or promote the formation of macromolecular assemblies. Aberrant protein kinase function arising from mutation or viral subversion mechanisms gives rise to cellular dysfunctions that underlie numerous human diseases. The ability to counteract aberrant protein kinase function through the use of small molecule therapeutics has validated the protein kinase as a drugable target. The pervasiveness of protein kinases as regulators of cellular biology, stems from a plasticity of structure that allows for the diversification of catalytic switching and substrate recognition mechanisms. To date only a small fraction of eukaryotic protein kinases have been structurally characterized. In my lab, we are seeking to uncover the structural basis for novel catalytic switching, substrate recognition and down-stream phospho-regulatory mechanisms. Our long-term goal is to make use of what we learn about protein kinases and phospho-regulatory systems to develop drugs to treat disease.